Published Online
on August 6, 2009

A more recent version of this article appeared on November 1, 2009

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Original Article

A New Direction for Cardiac Regeneration Therapy: Application of Synergistically Acting Epicardium-Derived Cells and Cardiomyocyte Progenitor Cells.

Elizabeth M. Winter¹; Angelique A.M. van Oorschot¹; Bianca Hogers¹; Linda M. van der Graaf¹; Pieter Doevendans²; Robert E. Poelmann¹; Douwe E. Atsma¹; Adriana C. Gittenberger-de Groot^1,3 and Marie Jose Goumans¹

¹ Leiden University Medical Center, Leiden, The Netherlands;
² Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands

^* Corresponding author; email: a.c.gittenberger-de_groot{at}lumc.nl

Background—Adult human epicardium-derived cells (EPDCs), transplanted into the infarcted heart, are known to improve cardiac function, mainly through paracrine protection of the surrounding tissue. We hypothesized that this effect might be further improved if these supportive EPDCs were combined with cells that could possibly supply the ischemic heart with new cardiomyocytes. We therefore transplanted EPDCs together with cardiomyocyte progenitor cells (CMPCs) that can generate mature cardiomyocytes in vitro.

Methods and Results—EPDCs and CMPCs were isolated from human adult atrial appendages, expanded in culture, and transplanted separately or together into the infarcted mouse myocardium (total cell number: 4x10⁵). Cardiac function was determined six weeks later (9.4T MRI). Indicating a mutual effect, co-culturing increased proliferation rate and production of several growth factors. Co-transplantation resulted in further improvement of cardiac function compared to single cell type-recipients (p<0.05), which themselves demonstrated better function than vehicle-injected controls (p<0.05). However, in contrast to our hypothesis, no graft-derived cardiomyocytes were observed within 6 weeks survival, supporting that not only EPDCs, but also CMPCs acted in a paracrine manner. Since injected cell number and degree of engraftment were similar between groups, the additional functional improvement in the co-transplantation group can not be explained by an increased amount of secreted factors but rather by an altered type of secretion.

Conclusion—EPDCs and CMPCs synergistically improve cardiac function after myocardial infarction, probably instigated by complementary paracrine actions. Our results demonstrate for the first time that synergetically acting cells hold great promise for future clinical regeneration therapy.

Key Words: cells • myocardial infarction • transplantation • epicardium • synergism